A Genetic Approach to Defining the Role of Glucose in Vascular Remodeling

Abstract

The contributing role of glucose in vascular disease is controversial. The goal of this study was to use a genetic approach to test the hypothesis that increasing cellular glucose uptake was sufficient to alter vascular remodeling in response to injury. Two transgenic models were established harboring the insulin-independent glucose transporter (Glut1) under the control of the smooth muscle specific sm22alpha promoter (Sm22Glut1) and the ubiquitous beta-actin promoter (beta-actinGlut1). Glut1 protein in the aorta and glucose uptake in isolated aortic smooth muscle cells were significantly increased in both models (sm22Glut1 5183±141 cpm, beta-actinGlut1 8289±367 cpm, wild type 2059±239 cpm, p<0.05, n=3). Fasting blood glucose, non-esterified fatty acids, and insulin levels were unaffected. Up-regulation of Glut1 led to an increase in circulating matrix metalloproteinase-9 (MMP-9) (sm22Glut1 236±55 ng/mL, beta-actinGlut1 641±89 ng/mL, wild type 85±10 ng/mL, n=4-6, p<0.05). Vascular injury induced a marked increase in local MMP-9 expression in the lesion of both models along with a significant increase in the number of macrophages and a decrease in smooth muscle cells. In summary, the data suggest that increased cellular glucose uptake elevates circulating and local MMP-9 and promotes an inflammatory phenotype in the vessel. This study was supported by funding from the Lillehei Heart Institute.